Elsevier

Brain and Cognition

Volume 139, March 2020, 105511
Brain and Cognition

Inhibition deficits are modulated by age and CGG repeat length in carriers of the FMR1 premutation allele who are mothers of children with fragile X syndrome

https://doi.org/10.1016/j.bandc.2019.105511Get rights and content

Highlights

  • We examined inhibition skills in mother carriers of the FMR1 premutation.

  • Mid-range CGG repeats of ~80–100 were associated with greater inhibition deficits.

  • Older age was also linked with inhibition deficits, beyond the effect of CGG size.

  • Mid-range CGG’s and older age could be personalized risk factors for carriers.

Abstract

Individuals who carry a premutation (PM) allele on the FMR1 gene may experience executive limitations associated with their genetic status, including inhibition deficits. However, poor understanding of individualized risk factors has limited clinical management of this group, particularly in mothers who carry the PM allele who have children with fragile X syndrome (FXS). The present study examined CGG repeat length and age as factors that may account for variable expressivity of inhibition deficits. Participants were 134 carriers of the PM allele who were mothers of children with FXS. Inhibition skills were measured using both self-report and direct behavioral assessments. Increased vulnerability for inhibition deficits was observed at mid-range CGG lengths of approximately 80–100 repeats, with some evidence of a second zone of vulnerability occurring at approximately 130–140 CGG repeats. Risk associated with the genotype also became more pronounced with older age. This study identifies personalized risk factors that may be used to tailor the clinical management of executive deficits in carriers of the PM allele. Inhibition deficits may contribute to poor outcomes in carriers of the PM allele and their families, particularly in midlife and early old age, and clinical monitoring may be warranted.

Introduction

Over one million individuals in the United States are genetic carriers of a premutation (PM) allele on the Fragile X Mental Retardation-1 (FMR1) gene (Maenner et al., 2013). Carriers of the PM allele have 55–200 CGG repeats on the FMR1 gene on the X chromosome, which represents an expansion beyond the normal range of 6–54 CGG repeats (Maddalena et al., 2001). PM expansion of the FMR1 CGG sequence is associated with molecular genetic abnormalities, such as decreased production of the protein encoded by FMR1, Fragile X Mental Retardation Protein (FMRP; Kenneson et al., 2001, Oh et al., 2015, Primerano et al., 2002) and elevated levels of FMR1 mRNA (Garcia-Arocena and Hagerman, 2010, Kenneson et al., 2001, Tassone et al., 2000). Accumulating evidence now supports the PM allele as a genotype that is associated with clinical risk, although varying symptom severity and age of symptom onset, as well as incomplete penetrance, has made it difficult to pinpoint the full range of associated clinical features (Movaghar et al., 2019, Wheeler et al., 2017, Wheeler et al., 2014).

Delineating the phenotype as manifested in female carriers of the PM allele is of particular importance given that PM alleles are about twice as likely to occur in females compared to males (Hunter et al., 2014). Moreover, female carriers of the PM allele can pass an expanded version of the affected gene to their children, causing fragile X syndrome (FXS)—an inherited form of intellectual disability (Fu et al., 1991). Understanding the presentation of PM symptoms in mothers of children with FXS is critically important because the clinical effects of the PM allele may have implications not only for the mother’s health but also for her ability to care and advocate for her children living with FXS. Defining the clinical phenotype of carriers of the PM allele as manifested in mothers of children with FXS is essential to the development of family-centered treatments that target the specific needs of carriers of the PM allele and their families. Moreover, carriers of the PM allele who are mothers of children with FXS may be more vulnerable to poor outcomes in general, due to the combined effects of genetic risk coupled with the added environmental stressors associated with parenting a child with a disability (e.g., Seltzer et al., 2012). In sum, the clinical significance of the PM allele may be elevated among mothers of children with FXS due to the broader family context in which it occurs.

The FMR1 PM allele confers risk for two well-established genotype-specific conditions: Fragile X-Associated Primary Ovarian Insufficiency (FXPOI) and Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). FXPOI affects approximately 20% of female carriers of the PM allele and is characterized by early menopause, hormonal disruption, and fertility problems (Sullivan, Welt, & Sherman, 2011). FXTAS is a late-onset neurodegenerative disorders that occurs in approximately 17% of female carriers of the PM allele and is characterized by tremor, ataxia, cognitive decline, and associated neuropathological features that include white matter degeneration, global brain atrophy, and intranuclear inclusions throughout the cortex and brainstem (Greco et al., 2005, Halket et al., 2016, Rodriguez-Revenga et al., 2009). Other documented clinical consequences of the FMR1 PM genotype in women who have children with FXS include elevated risk for depression, anxiety, and physical health problems such as hypertension and migraines (Bourgeois et al., 2011, Hagerman and Hagerman, 2013, Roberts et al., 2016). Mild autism-related features, including difficulties with eye contact and the social use of language, are also elevated in this group (Klusek et al., 2019, Klusek et al., 2018, Losh et al., 2012).

Executive deficits in working memory, attention, and inhibition have been reported in female carriers of the PM allele, although the executive phenotype in females is controversial due to inconsistencies across reports (e.g., Hunter et al., 2008). Neuroimaging evidence from carriers of the PM allele lends support for executive deficits associated with this genotype, as evidenced by structural, microstructural, and functional differences in brain regions important for executive functions. For example, white matter abnormalities have been implicated in attenuated performance on a range of executive tasks (Gunning-Dixon & Raz, 2000) and are observed in frontal, parietal, and cerebellar pathways in both male and female carriers of the PM allele who do not have FXTAS (Battistella et al., 2013, Hashimoto et al., 2011b, Leow et al., 2014). Some reports have detected associations between white matter abnormalities in female carriers of the PM allele and FMR1-related molecular indices (mRNA levels and methylation of the FMR1 exon 1/intron 1 boundary), suggesting that these differences in brain structure may arise due to genetic risk associated with the PM allele (Shelton et al., 2017). White matter microstructure in the corpus callosum and cerebellar peduncles, and disruption of diffusion network measures in the left superior parietal cortex, have been reported as correlates of performance on executive functioning measures in female carriers of the PM allele who were asymptomatic for FXTAS (Leow et al., 2014, Shelton et al., 2017). Moreover, reduced activation in pre-frontal and frontal-parietal regions—areas important for executive function—has been observed in female carriers of the PM allele during completion of a various executive tasks and are associated with specific FMR1 molecular genetic markers (Hashimoto et al., 2011a, Kim et al., 2013). Overall, neuroimaging studies of female carriers of the PM allele suggest the presence of structural, microstructural, and functional differences in brain regions that are implicated in executive functions and which appear to be linked to FMR1-related molecular genetic alterations.

Behavioral studies of executive skills in female carriers of the PM allele suggest that deficits in inhibition, or the suppression of automatic or preplanned responses (Aron, 2011), are perhaps the most widely documented executive deficit. This body of evidence suggests poorer performance than matched controls on tasks requiring verbal, visual, or motor suppression of prepotent responses (Kraan et al., 2014b, Shelton et al., 2014, Yang et al., 2013). Yet, findings have been mixed, with some studies failing to detect inhibition differences in female carriers of the PM allele (see Hunter et al., 2008, Wheeler et al., 2017). Clarifying these discrepancies is important given that inhibition deficits can impact performance in social and occupational contexts, and are linked with a host of maladaptive behaviors including substance abuse, suicidal ideation, criminal conduct, and antisocial behavior (Feilhauer et al., 2012, Meza et al., 2016, Rubio et al., 2008, Tremblay et al., 1994, Verdejo-García et al., 2008).

One source of inconsistency in the extant literature may be variation due to measurement techniques. It has been argued that tasks that require rapid, on-line recruitment of executive skills have increased sensitivity to PM-associated executive difficulties relative to tasks that do not impose time constraints, underscoring the need for multimodal assessment in future work (e.g., Kraan et al., 2014a, Shelton et al., 2016). Discrepant findings may also be due, in part, to differing sample characteristics across studies, such as the age of the sample members. Many prior reports have focused on samples consisting of young-adult and middle-aged women, while evidence suggests that PM-associated symptoms may become more prominent at older ages. Age-related decline in cognitive-executive functioning has been suggested in some emerging reports. For example, older age is correlated with reduced language fluency and lower scores on magnitude comparison and numerical enumeration tasks in female carriers of the PM allele, but not among age-matched controls (Goodrich-Hunsaker et al., 2011a, Goodrich-Hunsaker et al., 2011b, Sterling et al., 2013).

However, few prior investigations have examined the impact of aging on inhibition skills specifically. In one report by Kraan, Hocking, Georgiou‐Karistianis, et al. (2014), a correlation between older age and verbal inhibition errors was detected in female carriers of the PM allele (n = 35), although the association did not survive correction for multiple comparisons. Few other investigations have focused on females, although age-inhibition associations have also been noted in male carriers of the PM allele (Hunter, Sherman, Grigsby, Kogan, & Cornish, 2012). Thus, the extant literature is inconclusive and follow-up is needed to better understand the profile of age-related vulnerability in female carriers of the PM allele.

The length of the PM CGG repeat expansion is another factor that may relate to variability in the expression of inhibition deficits. PM expansion of the CGG sequence leads to molecular genetic alterations such as elevated mRNA and decreased FMRP (Kenneson et al., 2001, Oh et al., 2015, Primerano et al., 2002). These changes in gene function are thought to underlie phenotypic expression (Hagerman & Hagerman, 2013) and may vary according to the length of the CGG repeat expansion within the PM range (Chen et al., 2003, Kenneson et al., 2001, Loesch et al., 2007, Sellier et al., 2014). Thus, the size of the CGG expansion may provide important information regarding individualized risk profiles, including risk for inhibition difficulties. One report by Shelton et al. (2014) detected a correlation between ocular-motor inhibition errors and CGG repeat length, where errors were the highest at the lower end of the PM range and decreased linearly as the length of the CGG expansion increased. However, evidence is mixed, as not all reports have detected CGG-related variation in inhibition skills (Kraan et al., 2014b, Yang et al., 2013). Notably, most prior studies have been limited by small samples that were characterized by poor representation at the low and high ends of the PM CGG range, and as a result were unable to test for nonlinear associations. This is critical because curvilinear CGG relationships have been reported relative to other aspects of PM phenotype, with risk for clinical involvement the highest at mid-range PM repeat lengths (approximately 80–110) and lower at the tails (Ennis et al., 2006, Klusek et al., 2018, Mailick et al., 2014, Roberts et al., 2009, Seltzer et al., 2012). Only one prior report has probed for nonlinear CGG-inhibition relationships, with inconclusive results. In a study of 37 female carriers of the PM allele, Klusek et al. (2018) detected a trend where verbal inhibition errors were the most pronounced in carriers with approximately 60–80 CGG repeats, decreased by degree from approximately 80–120 CGG repeats, and began to increase again at CGG repeat sizes greater than approximately 120. Follow-up studies incorporating larger sample sizes are needed to clarify potential CGG-related modulation of inhibition skills in female carriers of the PM allele.

The present study represents the largest investigation to date of inhibition skills in female carriers of the PM allele. Including a sample of over 130 carriers of the PM allele, we aim to clarify the effect of age and CGG repeat length on the expression of inhibition deficits in this group. We focused on carriers of the PM allele who are mothers of a child with FXS (hereafter referred to as “PM mothers of children with FXS”)—a subgroup of women who may be particularly vulnerable to poor outcomes due to the coupling of genetic risk with elevated stress exposure associated with parenting a child with a disability (e.g., Seltzer et al., 2012). The study of the clinical phenotype of PM mothers of children with FXS is of particular importance because of broader family context in which it occurs; mothers are often the primary caregiver for their children and the clinical effects of the PM allele in mothers can impact health and quality of life for both the mother as well as her children with FXS. To address potential measurement effects that may account for discrepancies across prior reports, we adopt a multimodal approach that incorporates both self-report and direct assessment indices of inhibitory control, including measurement of both response latency and errors. The effort to identify individual risk factors that relate to inhibition deficits in carriers of the PM allele is consistent with a personalized medicine approach and may have implications for understanding individual risk profiles and the eventual application of tailored counseling and prevention efforts. Our specific research questions were: (1) Are inhibition skills associated with FMR1 CGG repeat length in PM mothers of children with FXS?; (2) Is older age associated with poorer inhibition skills in PM mothers of children with FXS? Consistent with prior reports of vulnerability at mid-range PM CGG repeat lengths, we expected inhibition skills to be most impaired in mothers with CGG repeat lengths of approximately 80–110. We also hypothesized that older age would relate to greater inhibition difficulties.

Section snippets

Participants

Participants in the present study included 134 female carriers of PM allele who were biological mothers of a child with FXS. Participants were drawn from a larger ongoing research study, Family Adaptation to Fragile X Syndrome, which focused on the adaptation of families of adolescents and adults with FXS (Mailick et al., 2018, Seltzer et al., 2012, Smith et al., 2016). One hundred of the present sample of 134 participants were recruited in 2008 and have been studied four times since then. Data

Descriptive statistics

Descriptive statistics are presented in Table 2. The average CGG repeat length on the PM allele was 93, with a range of 67–138. Eight percent of the sample obtained Hayling response latency scores falling at or below the 5th percentile, which corresponds to scaled scores classified within the “Impaired”, “Abnormal”, or “Poor” ranges, as described in the test manual (Burgess & Shallice, 1997). Twenty-five percent obtained Hayling error scores falling at or below the 5th percentile. Five percent

Discussion

This study represents the largest multimodal investigation conducted to date of inhibition skills in PM mothers of children with FXS. We detected increased vulnerability for inhibition deficits among older mothers and those who carried mid-range CGG lengths of approximately 80–100 repeats. Results also suggest a possible increase in risk occurring at approximately 130–140 repeats. This study enhances understanding of older age and mid-range PM CGG repeat length as personalized risk factors that

CRediT authorship contribution statement

Jessica Klusek: Conceptualization, Methodology, Formal analysis, Visualization, Writing - original draft, Writing - review & editing. Jinkuk Hong: Conceptualization, Methodology, Formal analysis, Writing - review & editing. Audra Sterling: Conceptualization, Methodology, Writing - review & editing. Elizabeth Berry-Kravis: Investigation, Methodology, Writing - review & editing. Marsha R. Mailick: Conceptualization, Methodology, Resources, Investigation, Writing - review & editing, Supervision,

Acknowledgements

We are grateful to the women and families who participated in this research.

Funding

This work was supported by the National Institutes of Health [grant numbers R01HD082110, P30 HD003100-S1, U54 HD090256, R21DC017804, R03HD098291].

Data Statement

The dataset analyzed in this study is not publicly available. Due to the sensitive nature of the study, participants were assured data would be released in aggregate form only and raw data would not be shared.

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